Steroid alkali-metal enolates



Patented July 13, 1954 STEROID ALKALI-METAL ENOLATES John A. Hogg, Kalamazoo Township, Kalamazoo County, and William P. Schneider, Kalamazoo, Mich., assignors to The Upjohn Company, Kalamazoo, Mich, a corporation of Michigan No Drawing. Application August 21, 1952, Serial No. 305,707

10 Claims. 1

The present invention relates to certain steroid enols and metal enolates thereof and is more particularly concerned with 2l-alkoxyoxalyl-3,11- dihydroxy-- and 21a1koxyoxalyl-3,ll-diacyloxy- 16-pregnene-20-one and alkali-metal enolates thereof.

The novel compounds of the present invention are steroids represented in their keto-form by the following structural formula:

CH: o

CHa I wherein in the formulae, R is hydrogen or an acyl group, M is an alkali metal and R is alkyl and the R-O- groups at the 3 and 11 positions have either the alpha or beta configuration.

The process of the present invention involves condensation of 3,11-dihydroxyor 3,11-diacyloxy-lS-pregnene-20-one with an alkyl di-ester of oxalic acid in the presence of an alkali-metal base to produce a 21-alkoxyoxa1yl-3,11-dihydroxyor 21-alkoxyoxalyl 3,11 diacyloxy 16- pregnene 20 one alkali-metal enolate. Treatment with dilute acid produces the free enol, 21- alkoxyoxaly1-3,1l-dihydroxyor 21-alkoxyoxalyl- 3,11-diacyloxy-16-pregnene-20-one.

An object of the present invention is to provide novel 21 alkoxyoxalyl 3,11 dihydroxyor 21- alkoxyoxalyl 3,1l-diacyloxy 16 pregnene-20- ones and alkali-metal enolates thereof. Other objects of the present invention will be apparent to those skilled in the art to which this invention pertains.

The novel compounds of the present invention have utility as stable forms of the corresponding keto acids, keeping well, as convenient solids for long periods of storage. Their water solubility makes these compounds readily adaptable for further synthesis to reactions employing aqueous media. The correspondin enols, the acids which can readily be obtained by hydrolysis and the 21-acyloXy-3,1l-dihydroxyand 3,11,21- triacyloxy 16 pregnene 20-one compounds as shown in Examples 1A and 1B, furnish valuable intermediates for the preparation of adrenal cortical hormones. For example, cortisone acetate may be obtained in the following manner: 3a,1la-dihydroxy-2l-acetoxy-lB-pregnene- 20-one (Example 1B) is treated with a peracid, such as perbenzoic acid, to form a 16(1'7)-epox ide. The epoxide is then opened with hydrogen bromide and the resulting lfi-bromo-l'ia-hydroxy derivative is treated with zinc dust to remove the bromine and yield a 30,11a,l7a-trihydroXy-21- acetoxy-16-pregnane-20-one. Oxidation of this trihydroxy ketone with chromic acid in acetic acid yields 17a-hydroxy-21 acetoxy 16 pregnene-3,11,20-trione, a compound known in the art, which may be converted to cortisone acetate by the procedure of Kritchevsky et al., J. Am. Chem. Soc., 74, 483 (1952).

The novel compounds of the present invention which are of particular interest are those com pounds having the above generic formula wherein R is hydrogen or an acyl radical of a hydrocarbon carboxylic acid, preferably such acid containing up to eight carbon atoms, inclusive, and R is an alkyl radical, preferably lower alkyl radicals containing up to eight carbon atoms inclusive, and the alkali-metal enolates thereof.

Starting materials of the present invention are the 3,11-dihydroxyor 3,11-diacyloxy-l6-pregnene-ZO-ones which may be prepared from available 3,l1-dihydroxyor 3,11-diacyloxy-16-prcgnane-20-one [Gallagher et al., J. Biol. Chem., 165, 197 (1946); Reichstein et al., Helv. Chim. Acta, 27, 1287 (1944)] by bromination and dehydrobromination as shown in Preparation 1.

The configuration of the group at carbon atom three and eleven of the starting material does not influence the course of the reaction in the present invention. Starting compounds with either an aor ,B-configuration of the hydroxy or aoyloxy group at carbon atom three or eleven are equally operative. Since no change in configuration at carbon atom three and eleven takes place under the conditions of reaction, the configuration of the product is dependent on the starting material employed.

In carrying out the process of the present invention, a 3,1l-dihydroxy or 3,11-diacyloxy 16- pregnene--one is usually dissolved in the alkanol corresponding to the alkanol which is used in the formation of the selected starting ester of oxalic acid, or in a solvent which is non-reactive under the conditions of reaction, such as, for example, benzene or ether, and mixed with the selected alkyl di-ester of oxalic acid in the presence of an alkali-metal base. The di-esters of oxalic acid which are preferred in the method of the present invention are lower-alkyl esters containing from one to eight carbon atoms, in elusive. Of these the methyl and ethyl esters ar preferred. Alkali-metal bases which may be used include the alkali-metal alkoxides, the alkali metals, the alkali-metal hydrides, sodium amide, triphenylmethyl sodium, and others. Of these the sodium and potassium alkoxides are preferred. The selected alkali-metal base catalyses the condensation of the alkyl di-ester of oxalic acid with the 3,1l-dihydroxyor 3,11- diacyloxy-l6-pregnene-20-one and contributes the alkali-'netal moiety to the alkali-metal enolate. The alkali-metal alkoxide may be used solvent-free, dissolved or suspended in a nonreactive solvent, or in situ in the alkanol in which said alkali-metal alkoxide was formed. When potassium is used, it is usually used as th solution formed by its reaction with tertiary butyl alcohol according to procedure well known in the art.

The resulting reaction mixture is then allowed to stand at a temperature between about zero degrees centigrade and the boiling point of the reaction mixture, preferably at room temperature, for a period of between about onehalf hour and about ninety six hours, usually about one to four hours.

The thus-produced alkali-metal enolate may be separated by the addition of a large volume of an organic solvent in which the alkali-metal enolate is insoluble, such as, for example, ether, petroleum ether, hexane hydrocarbons or the like. The thus-recovered 2l-alkoxyoxalyl-3,11- dihydroxyor 2l-alkoxyoxalyl-3,ll-diacyloxy-16- pregnene-ZO-one alkali-metal enolate is usually obtained as an amorphous stable solid. Alternatively, it may be used, without isolation, as an intermediate in the synthesis of the corresponding 21-glyoxalic acid, or as an intermediate for the introduction of a 21-hydroxy or acyloxy group into 3,1l-dihydroxyor 3,11-diacyloxy-16- pregnene-ZO-one as described in procedures A and B of Example 1, or as the free enol by treatment of the alkali-metal enolate with dilute acid, such as hydrochloric acid, sulfuric acid or the like, as described in procedure C of Example 1.

The following examples are given to illustrate the process and products of the present invention and are not to be construed as limiting.

PREPARATION 1.3a,11aminmmoxY-ldrammrun QO-ONE To a solution of 165 milligrams (0.5 millimole) of :,11udihydroxypregnane-20-one in 25 milliliters of chloroform was added a solution of eight milligrams (0.5 millimole) of bromine in five milliliters of chloroform. The addition was done dropwise and at such a rate that each drop was decolorized before the next drop was added. When the addition was complete, the solvent was removed under reduced pressure and the residue was dissolved in ten milliliters of pyridine. The pyridine solution was then refluxed for eight hours, cooled and poured into water. The aqueous solution was extracted with chloroform and the chloroform solution was washed with dilute sulfuric acid. and water. After drying over an- 5 hydrous sodium sulfate, the chloroform was evaporated off leaving a pale yellow semi-crystalline residue which was ehromatographed over ten grams of Florisil (magnesium silicate). The chromatogram was developed with six 150-milliliter portions of solvent as follows:

Weight of Fraction Solvent Residue Benzene Benzene-ether (9:1

Benzene-ether (8:2) Benzene-ether (1:1) Ether Acetone The eluates were evaporated to dryness and the residue was weighed. Fraction 4, containing 76.5 milligrams, was crystallized from ethyl acetate-hexane to yield fifteen milligrams of galladihydroxy-lfi-pregnene-ZO-one; melting point 177.5 to 180 degrees centigrade.

AnaZysis.Per cent calculated for Call-T3203: C, 75.86; H, 9.70. Found: C, 75.47; H, 10.08.

In a manner substantially identical with that of Preparation 1, the following compounds are prepared by reaction of the selected 3,1l-dihydroxyor 3,11-diacyloxy-16-pregnane-20-one with bromine and subsequent dehydrobromination: 35,11a-dihydroxy lfi-pregnene 20-one; BaJIc-dihydroXy lfi-pregnene-ZO-one; 318,1lfidihydroxy-16-pregnene-20-one and the diformates, diacetates, dipropionates, diisopropionates, dibutyrat-es, diisobutyrates, divalerates, diisovalerates, dicaproates, dioenanthylates, dicaprylates and dibenzoates of the above described diols.

Example 1.Sodium enolate of ZI-ethoacyoxalyl- 311,110;-dihydroazy-lfi-pregnene-ZO-one A mixture of 3.4 milliliters of a 3.4 N solution of methanolic sodium methoxide, twenty milliliters of dry benzene and 0.45 milliliter of absolute ethanol, was distilled until approximately eight milliliters of distillate had been collected and the mixture then cooled. Two and threetenths milliliters of ethyl oxalate was then added thereto with stirring followed by a solution of 3.32 grams (0.01 mole) of 3m,11a-dihydroxy-16- pregnene-ZO-one in a mixture of thirty milliliters of dry benzene. The reaction mixture was stirred for two hours. Fifty-five milliliters of anhydrous ether was then added thereto and the whole stirred for an additional hour, whereafter an additional 110 milliliters of anhydrous ether was added. The ivory colored sodium enolate of 2l-ethoxyoxalyl 305,111: dihydroxy l6 pregnene-20-one thus precipitated was filtered, washed with ether, and dried. The presence of a sodium enolate in the structure was verified by the extreme solubility of the product in water and by a positive ferric chloride test for enols as exhibited by the formation of a bright red color when the product was dissolved in aqueous and alcoholic solutions of ferric chloride. The theoretical structure was further verified by infrared and ultraviolet absorption spectra.

A. 21-GLYOXALIC ACID or 3a,11a-DIHYDROXY-l6- RREGNENE-20-ONE Five hundred milligrams of the sodium enolate of 21-ethoxyoxalyl-3a,11a-dihydroxy l6 pregnene-20-one, obtained above, was dissolved in a solution of seventy milligrams of potassium hydroxide in fifteen milliliters of a solution composed of equal parts of water and alcohol, whereafter the whole was heated for fifteen minutes on a steam bath. The cooled solution was then filtered and upon acidification there was slowly deposited a white crystalline precipitate of the 2l-glyoxalic acid of 3a,11a-dihydroxy-l6-preg nene-2o-one. Infrared analysis of said compound in solution (chloroform) verified the theoretical structure.

B. 3a,11a-DIHYDROXY-2l-ACETOXY-lG-PREGNENE- ZO-ONE To a solution of 1.73 grams (0.004 mole) of the sodium salt of 21-ethoxyoxalyl-3a,lla-dihydroxy-16-pregnene-20-one dissolved in 25 milliliters of methanol and cooled in an ice-bath was added dropwise, with stirring, over a period of approximately one hour, a solution of 1.05 grams (0.004 mole) of iodine dissolved in forty milliliters of methanol while maintaining the reaction temperature between minus fifteen and minus twenty degrees centigrade. The reaction mixture thus-produced was stirred for eighty minutes at a temperature of about minus fifteen degrees centigrade whereafter 1.2 milliliters of a 3. N methanolic sodium methoxide solution was added thereto. Stirring was continued at zero degrees centigrade for one hour and the thus-produced 30,lloc-dlhYdI0XY 21 iodo-16- pregnene-20-one was precipitated by the dropwise addition or" 150 milliliters of water to the reaction mixture while maintaining the reaction temperature at zero degrees centigrade for the hour required to complete the addition. Twenty grams of sodium chloride was then dissolved in the reaction mixture and the product filtered, washed with water, and dried in a vacuum desiceater. The thus-isolated 3a,11 x-dihydroxy-21 iodo-ic-pregnene-zc-one was converted without further purification to 3u,11a-dihydroxy-2lacetoxy-pregnene-ZO-one as shown below.

To a freshly prepared mixture composed of twenty grams of potassium bicarbonate, twelve grams of glacial acetic acid and ten milliliters of acetone was added the 3a,11m-dihydroxy-21- i.odo-16pregnene-20-one obtained above dissolved in 100 milliliters of acetone. The mixture was heated under refluxing conditions for one hour Whereafter the mixture was kept at room temperature for 2.5 days. The inorganic solids were removed by filtration and washed with milliliters of acetone. The filtrate and wash were combined and the acetone removed by evaporation. The residue was extracted with three fifty-milliliter portions of warm ethyl ace tate which were then combined, washed with a dilute sodium thiosulfate solution and water, and finally dried over anhydrous sodium sulfate. The dry ethyl acetate was distilled in vacuo and the residue was dissolved in a small portion of benzene and chromatographed. Infrared analysis confirmed the structure of the 3a,110c-dihy droxy-Z1-acetoxy-1G-pregnene-ZO-one thus obtained.

c. 21-ETHOXYOXALYL-3u,llu-DIHYDROXY-lfi- PREGNENE-ZO-ONE Five hundred milligrams of the sodium enolate of 21-ethoxyoxalyl-3a,1la-dihydroxy 16 pregnene-QO-one were dissolved and suspended in twenty milliliters of water. Ten milliliters of ten percent hydrochloric acid were added and the precipitate which separated collected on filter paper, washed with water and dried in a vacuum desiccator over Drierite (anhydrous calcium sulfate). Infrared analysis confirmed the structure of the 21-ethoxyoxalyl-3a,11a-dihydroxy l6-pregnene-20-one.

Example 2.-Sodium enolate of 21 -metho.ryoxalyl-aJlwdihydrozw-16-pregnene-20-one Using essentially the procedure described in Example 1, 30,1la-dihydroxy-lfi-pregnene-ZO- one is converted to the sodium enolate of 21- methoxyoxalyl 30,1loc dihydroxy l6 pregnene-ZO-one by reaction with methyl oxalate and sodium in absolute methanol. The resulting sodium enolate is converted, as with the 21-ethoxyoxalyl compound, to the zl-glyoxalic acid of 30,11on-dlhYd10Xfy' 16 pregnene 20 one and 3 x,1lot-dihYdlOXY-Zl-ELCBtOXY 16 pregnene-ZO- one and 21-methoxyoxalyl-3u,lla-dihydroxy-lfipregnene-ZO-one according to the procedure of Examples 1A, 1B and 1C.

Example 3.-S0dium enolate of 21 -methor1'- oxalyl3fl,11u-dihydroxy-ld-pregnene-ZO-one Using essentially the procedure described in Example 1, 3 3,11u-dihydroxy-16-pregnene-20- one is converted to the sodium enolate of 21- methoxyoxalyl 3fi,1loc dihydroxy 16 pregnene-ZO-one by reaction with methyl oxalate and sodium in absolute methanol. The resulting sodium enolate is converted, as with the 2l-ethoxyoxalyl compound, to the 21-glyoxalic acid of 3 8,11 dihydroxy 16 pregnene-20-one, 21- acetoxy-3,8,1la-dihydroxy-lfi-pregnene 20 one and 21-methoxyoxalyl 3,6,11a dihydroxy-lfipregnene-ZO-one according to the procedure of amples 1A, 1B and 1C.

Example 4.Po=tassium enolate of ZI-ethozryoxaZyZ-3,B,1lc-dihydroasy-I6-pregnene-20-one Example 5.Potassium enolate of ZI-ethoscy- 0:calyl-3a,11a-diaoetoxy-I6-pregnene-20-o-ne Using essentially the procedure described in Example 1, 30;,11a-diacetoxy-16-pregnene-20- one is converted to the sodium enolate of 21- ethoxyoxalyl 30:,1lu-diacetoxy-IG-pregnene-ZO- one by reaction with ethyl oxalate and potassium in tertiary butyl alcohol.

In a manner substantially identical with that of Examples 1 through 5, the following compounds are prepared by reaction of the selected 3,11-dihydroxyor 3,1l-diacyloxy-lS-pregnene- 20-one with the appropriate alkyl oxalate and sodium or potassium alkoxide in an alkanol or non-reactive solvent medium: sodium enolate of 21 propoxyoxalyl 30:,110: dihydroxy-16-preg nene-20-one, sodium enolate of 21-butoxyoxalyl- 30;,11a-dihydroxy-lfi-pregnene 20 one, sodium enolate of 21amyloxyoxalyl-3a,1la-dihydroxy- 16-pregnene-20-one, the sodium enolate of 21- hexyloxyoxalyl-3u,1la-dihydroxy-lfi pregnene- 20-one, the sodium enolate of 21-hepytloxyoxalyl-3a,11a-dihydroxy-16-pregnene-20-one, the

sodium enolate of 21-octyloxyoxalyl-3a,1lu-dihydroxy-lG-pregnene 20 one, the corresponding 313,110: isomers, the 30511 6 isomers and the 35,115 isomers, the potassium analogues of these and like compounds and specifically the (ii-esters of the 3,11w-diols above, such as the diformate, diacetate, dipropionate, dibutyrate and diisobutryate, divalerate and diisovalerate, dicaproate, dioenanthylate, dicaprylate and dibenzoate, and similar related compounds.

It is to be understood that the invention is not to be limited to the exact details or exact compounds shown and described as obvious modi fications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. A compound selected from the group consisting of (1) 2l-lower-alkoxyoxalyl-3,11-dihydroxy-16-pregnene-20-one, represented by the following formula Ac-O wherein Ac is the acyl radical of a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive, and (4) a1ka1i-metalenolate thereof.

2. The sodium enolate of 2l-lower alkoxyoxalyl-3,l1-dihydroxy-16-pregnene-20-one.

3. The potassium enolate of 21-lower alkoxyoxalyl-3,11-dihydroxy-16-pregnene-20-one.

4. The sodium enolate of 2l-lower alkoxyoxalyl 3,11 diacyloxy 16 pregnene 20 one, wherein the acyloxy group is of the formula AcO, Ac being the radical of a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive.

5. The potassium enolate of 21-lower alkoxyoxalyl 3,11 diacyloxy 16 pregnene 20 one, wherein the acyloxy group is of the formlda AcO, Ac being the radical of a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive.

6. The sodium enolate of 21-methoxyoxalyl- 304,1la-dihydroxy-l6-pregnene-20-one.

'7. The sodium enolate of 2l-ethoxyoxalyl- 3a,1la-dihydroxy-16-pregnene-20-one.

8. 21 ethoxyoxalyl-3a,lla-dihydroxy-lfi-pregnene-ZO-one.

9. The potassium enolate of 21-ethoxyoxalyl- 3,1,1lm-diacetoxy-16-pregnene-20-one.

10. The sodium enolate of 2l-methoxyoxaylyl- 33,1la-dihydroxy-16-pregnene-20-one.

No references cited. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (1) 21-LOWER-ALOXYOXALYL-3,11-DIHYDROXY-16-PREGNENE-20-ONE, REPRESENTED BY THE FOLLOWING FORMULA 